The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Statins inhibit HMG-CoA reductase from catalyzing this conversion. As such, statins are collectively potent lipid lowering agents.
Atorvastatin calcium, disclosed in U.S. Pat. No. 5,273,995 which is incorporated herein by reference, is currently sold as Lipitor® having the chemical name [R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate and the formula

Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase. As such, atorvastatin calcium is a potent lipid-lowering compound and is thus useful as a hypolipidemic and/or hypocholesterolemic agent, as well as in the treatment of osteoporosis, benign prostatic hyperplasia (BPH), and Alzheimer's disease.
A number of patents have issued disclosing atorvastatin, formulations of atorvastatin, as well as processes and key intermediates for preparing atorvastatin. These include: U.S. Pat. Nos. 4,681,893; 5,273,995; 5,003,080, 5,097,045; 5,103,024; 5,124,482; 5,149,837; 5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,280,126; 5,397,792; 5,342,952; 5,298,627; 5,446,054; 5,470,981; 5,489,690; 5,489,691; 5,510,488; 5,686,104; 5,998,633; 6,087,511; 6,126,971; 6,433,213; and 6,476,235, which are herein incorporated by reference.
Atorvastatin can exist in crystalline, liquid crystalline and non-crystalline and amorphous forms.
Crystalline forms of atorvastatin calcium are disclosed in U.S. Pat. Nos. 5,969,156 and 6,121,461, which are herein incorporated by reference. Further crystalline forms of atorvastatin are disclosed U.S. Pat. No. 6,605,729 which is herein incorporated by reference.
Additionally, a number of published International Patent Applications have disclosed crystalline forms of atorvastatin, as well as processes for preparing amorphous atorvastatin. These include: WO 00/71116; WO 01/28999; WO 01/36384; WO 01/42209; WO 02/41834; WO 02/43667; WO 02/43732; WO 02/051804; WO 02/057228; WO 02/057229; WO 02/057274; WO 02/059087; WO 02/083637; WO 02/083638; WO 03/011826; WO 03/050085; WO 03/070702; and WO 04/022053.
It has been disclosed that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Konno, T., Chem. Pharm. Bull., 1990; 38:2003-2007). For some therapeutic indications one bioavailability pattern may be favored over another.
Variations in dissolution rates can make it advantageous to produce atorvastatin formulations in either crystalline or amorphous forms. For example, for some potential uses of atorvastatin (e.g., acute treatment of patients having strokes as described in Takemoto, M.; Node, K.; Nakagami, H.; Liao, Y.; Grimm, M.; Takemoto, Y.; Kitakaze, M.; Liao, J. K., Journal of Clinical Investigation, 2001; 108(10): 1429-1437) a rapid onset of activity may be highly beneficial in improving the efficacy of the drug.
The preparation of solid formulations of atorvastatin is described in U.S. Pat. Nos. 5,686,104 and 6,126,971. In the process described therein, atorvastatin is combined with a stabilizing additive, such as, an alkaline earth metal salt, and excipients and subjected to wet granulation using a combination of water and a surfactant (Tween™ 80). Because alkaline earth metal salt additives can affect atorvastatin bioavailability, there remains a need to provide atorvastatin in a wet granulated composition wherein said composition is substantially free of an alkaline earth metal salt additive. Similarly, it can be desirable to minimize the use of any alkalizing agent additives in a composition of atorvastatin to avoid potential bioavailability issues and avoid interactions when the drug is used in combination dosage forms with other drugs.
Concurrently filed United States Patent Applications, commonly owned, Ser. No. 10/828,419 discloses a unit dosage form comprising atorvastatin or a pharmaceutically acceptable salt thereof prepared without a granulation step and Ser. No. 10/828,398 discloses a dry-granulated pharmaceutical composition comprising atorvastatin or a pharmaceutically acceptable salt thereof.
In preparation and storage of dosage forms of atorvastatin, it is important to provide the active drug in a pure form. Moreover, it is desirable to achieve this high purity and stability with as simple a formulation as possible. There remains a need to provide simple formulations and processes for preparation of unit dosage forms of atorvastatin that have low levels of impurities. Moreover, there remains a need to provide atorvastatin formulations suitable for unit dosage forms whereby adequate drug purity, stability, and desired dissolution rate and bioavailability is provided with minimal addition of alkalizing agents.
One preferred unit dosage form for atorvastatin is a tablet. For active drugs in tablets to be rapidly absorbed once swallowed, it is generally important for the tablet to disintegrate rapidly once exposed to fluids in the gastrointestinal tract. At the same time, it is important that the tablets be sufficiently hard that they do not fracture or chip during manufacturing, handling or storage. These seemingly contradictory needs can be met by addition of disintegrants to the composition. A number of disintegrants for compositions of atorvastatin have been disclosed in the prior art including calcium carboxymethylcellulose, starch and croscarmellose sodium (see U.S. Pat. Nos. 5,686,014 and 6,126,971). When using atorvastatin with minimal levels of an alkalizing additive or an alkaline earth metal salt additive, we have unexpectedly found that with the standard wet granulation process, only certain disintegrants provide for tablets of atorvastatin with acceptable purity. This is especially unexpected since the disintegrant used in commercial formulations (croscarmellose sodium) was found to be unacceptable for wet granulations of amorphous atorvastatin with minimal levels of added alkalizing additives or alkaline earth metal salt additives. Moreover, this stability is unexpectedly maintained even when the atorvastatin is in an amorphous form. In addition to formulation improvements, we have developed wet granulation processes for incorporation of disintegrants into formulations that provide atorvastatin with high purity, even for disintegrants that provide poor stability with the standard process.
We have further found that when using a wet granulation of atorvastatin (especially non-crystalline atorvastatin), purity of the drug can be improved by addition of volatile bases to the granulation solvent. These volatile bases provide for improved purity of the drug in the dosage form, yet are not themselves present in the final dosage form, and as such cannot affect the bioavailability.
Therefore, it is an object of the present invention to provide a stable dosage form of atorvastatin having a good disintegration rate and bioavailability. It is a further object of the present invention to provide a stable and pure composition of atorvastatin with minimal levels of alkaline earth metal salt additives or other added alkalizing agents in the composition.